Sleep fragmentation (SF, sleep interrupted by repeated arousals/awakenings) and chronic intermittent hypoxia (CIH) are the two primary events associated with obstructive sleep apnea (OSA). In the last four years of this project, we demonstrated that CIH enhances both respiratory long-term facilitation (LTF, a persistent increase in respiratory activity after episodic hypoxia) and hypoxic phrenic response in rats, and the CIH-induced enhancement requires serotonergic mechanisms. In contrast to CIH, SF, characterized by a significant loss of deep sleep but not total sleep time, has been much less studied, particularly with respect to respiratory control. Our preliminary data suggest that SF, achieved by periodic, forced locomotion in a rotating drum, eliminates LTF, counteracts the CIH effect on LTF and impairs chemo-reflexes to hypoxia and hypercapnia, and that the SF-induced impairments require adenosinergic mechanisms. Our working model is that SF increases extracellular adenosine levels (may also up-regulate adenosine A1 receptors) near respiratory motoneurons, which reduces glutamate and serotonin release from nerve terminals via A1 receptor-mediated pre-synaptic inhibition, thus impairing chemo-reflexes and LTF, respectively. Three specific aims are proposed. Aim 1 will test the hypothesis that SF eliminates ventilatory, hypoglossal and phrenic LTF, and impairs ventilatory chemo-reflexes. Aim 2 will test the hypothesis that SF impairs the CIH effect on LTF. Aim 3 will investigate the role of A1 receptors in the SF-induced impairments by testing the hypotheses that: 1) the SF-impaired LTF and chemo-reflexes are restored by the A1 receptor antagonist 8-CPT (8-cyclo-pentyl-theophylline, i.p.); 2) the impaired phrenic LTF is also restored by microinjection of 8-CPT into the phrenic motor nucleus region (PMN); 3) phrenic LTF is abolished by microinjecting A1 receptor agonist into PMN; 4) SF increases adenosine levels near respiratory motoneurons; and 5) SF inhibits the episodic hypoxia-induced serotonin release in PMN, which is restored by A1 receptor antagonism. The information derived from the proposed studies will contribute to our understanding of the neural plasticity in respiratory motor control and provide evidence in favor of the notion that SF may exacerbate OSA via certain impaired ventilatory control mechanisms.